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OBJECTIVE: Lithium augmentation is an established strategy in the treatment of refractory depression, but little is known about predictors of response and its mode of action. There is increasing evidence that low thyroid function indices within the normal range are associated with a poorer treatment response to antidepressants, but previous studies on the hypothalamic-pituitary-thyroid (HPT) system during lithium augmentation provide inconclusive results and have methodological limitations. This study aimed at exploring the role of thyroid function in lithium augmentation and used a prospective design that included a homogeneous sample of inpatients with unipolar major depressive disorder. METHODS: In 24 euthyroid patients with a major depressive episode who had not responded to antidepressant monotherapy of at least 4 weeks, we measured serum thyroid-stimulating hormone (TSH), total triiodothyronine (T3) and total thyroxine (T4) before (baseline) and during lithium augmentation therapy (follow-up). The time point of the endocrinological follow-up depended on the status of response, which was assessed weekly with the Hamilton Depression Rating Scale, 17-item version (HDRS17). Responders were reassessed immediately after response was determined, and non-responders after 4 weeks of lithium augmentation. RESULTS: There was a statistically significant change in thyroid system activity during lithium augmentation, with an increase of TSH levels and a decrease of peripheral T3 and T4 levels. However, there were no differences in any of the HPT hormones between responders and non-responders at baseline or at follow-up. CONCLUSIONS: The decrease of thyroid system activity during lithium treatment reflects the well-established 'antithyroid' properties of lithium. However, it appears that thyroid status does not predict response to lithium augmentation in euthyroid patients before treatment. [ABSTRACT FROM AUTHOR]

Background: The phenomenon of preventing the recurrences of mood disorders by the long-term lithium administration was discovered sixty years ago. Such a property of lithium has been unequivocally confirmed in subsequent years, and the procedure makes nowadays the gold standard for the pharmacological prophylaxis of bipolar disorder (BD). The efficacy of lithium prophylaxis surpasses other mood stabilizers, and the drug has the longest record as far as the duration of its administration is concerned. The continuation of lithium administration in case of good response could be a lifetime and last for several decades. The stability of lithium prophylactic efficacy in most patients is pretty steady. However, resuming lithium after its discontinuation may, in some patients, be less efficient., Main Body: In the article, the clinical and biological factors connected with the prophylactic efficacy of long-term lithium administration are listed. Next, the adverse and beneficial side effects of such longitudinal treatment are presented. The main problems of long-term lithium therapy, which could make an obstacle to lithium continuation, are connected with lithium's adverse effects on the kidney and, to lesser extent, on thyroid and parathyroid functions. In the paper, the management of these adversities is proposed. Finally, the case reports of three patients who have completed 50 years of lithium therapy are described., Conclusions: The authors of the paper reckon that in the case of good response, lithium can be given indefinitely. Given the appropriate candidates for such therapy and successful management of the adverse effects, ultra-long term lithium therapy is possible and beneficial for such patients., (© 2024. The Author(s).)

Background: Suicidal ideation and suicide attempts present a serious public health concern among adolescents and young adults. School-based suicide prevention programs are a key tool for addressing this problem. However, more research is necessary to assess their effectiveness, acceptability, and safety. In response, the HEYLiFE suicide prevention program was developed to enhance help-seeking, reduce stigma towards suicidal peers and diminish risk factors for suicidality. This article presents the evaluation findings of the HEYLiFE program in German secondary schools., Methods: We conducted a randomized-controlled trial measuring short-term pre-post within-group effects in the intervention group only and mid-term effects at 6-months-follow-up compared to a waitlist-control group. Schools were assigned randomly to the intervention or control group (no blinding). We recruited students ≥12 years of age. Primary outcomes were knowledge about suicidality, attitudes towards suicidality, stigma towards a suicidal peer, help-seeking intentions and behaviours, risk factors for suicidality. The data was analysed with linear mixed models and generalized linear mixed models., Results: A total of N = 745 students participated (n = 353 intervention group, n = 392 control group). We observed favourable short-term effects on knowledge, attitudes towards suicidality and fear towards a suicidal peer. Unexpectedly, the program also led to an increase in desire for social distance and a decrease in prosocial emotions towards a suicidal peer. The mid-term effects of the program were exclusively favourable, resulting in enhanced attitudes towards help-seeking while protecting from a sharper rise in risk-factors for suicidality and from an increase in social distance. The program had more favourable effects on females and on students aged >13 years. The program was well-received by the students, and no serious adverse events were reported., Conclusions: These findings demonstrate the effectiveness of the HEYLiFE universal suicide prevention program in addressing variables associated with suicidal ideation and suicide attempts among adolescents on the mid-term. The short-term negative effects on stigma and more negative effects on males should be addressed in the future. Future evaluation studies should examine its effects on suicidality and its effectiveness within populations at high risk., Trial Registration: The study was preregistered in the German Clinical Trials Register (registration number: DRKS00017045; registration date: 02/04/2019)., (© 2024. The Author(s).)

Background: Lithium is the gold standard prophylactic treatment for bipolar disorder. Most clinical practice guidelines recommend regular calcium assessments as part of monitoring lithium treatment, but easy-to-implement specific management strategies in the event of abnormal calcium levels are lacking., Methods: Based on a narrative review of the effects of lithium on calcium and parathyroid hormone (PTH) homeostasis and its clinical implications, experts developed a step-by-step algorithm to guide the initial management of emergent hypercalcemia during lithium treatment., Results: In the event of albumin-corrected plasma calcium levels above the upper limit, PTH and calcium levels should be measured after two weeks. Measurement of PTH and calcium levels should preferably be repeated after one month in case of normal or high PTH level, and after one week in case of low PTH level, independently of calcium levels. Calcium levels above 2.8 mmol/l may require a more acute approach. If PTH and calcium levels are normalized, repeated measurements are suggested after six months. In case of persistent PTH and calcium abnormalities, referral to an endocrinologist is suggested since further examination may be needed., Conclusions: Standardized consensus driven management may diminish the potential risk of clinicians avoiding the use of lithium because of uncertainties about managing side-effects and consequently hindering some patients from receiving an optimal treatment., (© 2022. The Author(s).)

Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries., Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun's electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries)., Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01., Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed., (© 2021. The Author(s).)

Background: Suicide risk of psychiatric patients has proven to be strongly increased in the months after discharge from a psychiatric hospital. Despite this high risk, there is a lack of systematic research on the causes of this elevated suicide risk as well as a lack of treatment and intervention for patients at high risk after discharge. The main objective of this pilot study is, firstly, to examine the factors contributing to the elevated suicide risk and, secondly, to investigate whether an additional setting of care starting at discharge may reduce suicidality., Methods: In this multi-centre pilot study, treatment as usual is complemented by an additional 18-month post-discharge setting of care for psychiatric patients at high risk for suicide. Two groups of patients differing in the amount of post-discharge personal contacts will be compared. One group of patients will be offered continuous personal contacts after discharge (months 1-6: monthly contacts; months 6-18: every 2 months) while another group of patients will receive contacts only at months 6, 12, and 18 after discharge. Data on suicidality, as well as associated with other symptoms, treatment, and significant events, will be collected. In the case of health-related severe events, the setting of care allows the patient to have the opportunity to connect with the doctor or therapist treating the patient., Discussion: The results of this study will contribute to identifying critical factors raising suicide risk after discharge and will demonstrate the potential influence on suicide prevention of a setting of care with regular personal contact after discharge., Trial Registration: ZMVI1-2517FSB135 - funded by the German Federal Ministry of Health., Competing Interests: Competing interestsUL and DR are part of the editorial team of BMC Psychiatry. The other authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: Symptoms of anxiety co-occur in a variety of disorders including in depressive episodes of bipolar disorder and in patients with thyrotoxicosis. Treatment of refractory bipolar disorder with supraphysiologic doses of levothyroxine (L-T4) has been shown to improve the phenotypic expression of the disorder and is associated with an increase of circulating thyroid hormones. However, it might be associated with somatic and mental adverse effects. Here we report the investigation of the influence of treatment with supraphysiologic doses of L-T4 on symptoms of anxiety in patients with refractory bipolar depression., Methods: Post-hoc analysis from a 6-week, multi-center, randomized, double-blind, placebo-controlled study of the effects of supraphysiologic L-T4 treatment on anxiety symptoms in bipolar depression. Anxiety symptoms were measured weekly with the Hamilton anxiety/somatization factor (HASF) score of the Hamilton Depression Rating Scale (HAMD) and the State- and Trait Anxiety Inventory (STAI)., Results: Treatment of both groups was associated with a significant reduction in anxiety symptoms (p < 0.001) with no statistical difference between groups (LT-4: from 5.9 (SD = 2.0) at baseline to 3.7 (SD = 2.4) at study end; placebo: from 6.1 (SD = 2.4) at baseline to 4.4 (SD = 2.8) at study end; p = 0.717). Severity of anxiety at baseline did not show a statistically significant correlation to the antidepressive effect of treatment with supraphysiologic doses of L-T4 (p = 0.811). Gender did not show an influence on the reduction of anxiety symptoms (females: from 5.6 (SD = 1.7) at baseline to 3.5 (SD = 2.4) at study end; males: from 6.1 (SD = 2.3) at baseline to 4.0 (SD = 2.4) at study end; p = 0.877)., Conclusions: This study failed to detect a difference in change of anxiety between bipolar depressed patients treated with supraphysiologic doses of L-T4 or placebo. Comorbid anxiety symptoms should not be considered a limitation for the administration of supraphysiologic doses of L-T4 refractory bipolar depressed patients. Trial registration ClinicalTrials, ClinicalTrials.gov identifier: NCT01528839. Registered 2 June 2012-Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT01528839.

Background: Lithium is recommended as a first line treatment for bipolar disorders. However, only 30% of patients show an optimal outcome and variability in lithium response and tolerability is poorly understood. It remains difficult for clinicians to reliably predict which patients will benefit without recourse to a lengthy treatment trial. Greater precision in the early identification of individuals who are likely to respond to lithium is a significant unmet clinical need., Structure: The H2020-funded Response to Lithium Network (R-LiNK; http://www.r-link.eu.com/ ) will undertake a prospective cohort study of over 300 individuals with bipolar-I-disorder who have agreed to commence a trial of lithium treatment following a recommendation by their treating clinician. The study aims to examine the early prediction of lithium response, non-response and tolerability by combining systematic clinical syndrome subtyping with examination of multi-modal biomarkers (or biosignatures), including omics, neuroimaging, and actigraphy, etc. Individuals will be followed up for 24 months and an independent panel will assess and classify each participants' response to lithium according to predefined criteria that consider evidence of relapse, recurrence, remission, changes in illness activity or treatment failure (e.g. stopping lithium; new prescriptions of other mood stabilizers) and exposure to lithium. Novel elements of this study include the recruitment of a large, multinational, clinically representative sample specifically for the purpose of studying candidate biomarkers and biosignatures; the application of lithium-7 magnetic resonance imaging to explore the distribution of lithium in the brain; development of a digital phenotype (using actigraphy and ecological momentary assessment) to monitor daily variability in symptoms; and economic modelling of the cost-effectiveness of introducing biomarker tests for the customisation of lithium treatment into clinical practice. Also, study participants with sub-optimal medication adherence will be offered brief interventions (which can be delivered via a clinician or smartphone app) to enhance treatment engagement and to minimize confounding of lithium non-response with non-adherence., Conclusions: The paper outlines the rationale, design and methodology of the first study being undertaken by the newly established R-LiNK collaboration and describes how the project may help to refine the clinical response phenotype and could translate into the personalization of lithium treatment.

Background: The world population is aging and the number of older adults with bipolar disorder is increasing. Digital technologies are viewed as a framework to improve care of older adults with bipolar disorder. This analysis quantifies Internet use by older adults with bipolar disorder as part of a larger survey project about information seeking., Methods: A paper-based survey about information seeking by patients with bipolar disorder was developed and translated into 12 languages. The survey was anonymous and completed between March 2014 and January 2016 by 1222 patients in 17 countries. All patients were diagnosed by a psychiatrist. General estimating equations were used to account for correlated data., Results: Overall, 47% of older adults (age 60 years or older) used the Internet versus 87% of younger adults (less than 60 years). More education and having symptoms that interfered with regular activities increased the odds of using the Internet, while being age 60 years or older decreased the odds. Data from 187 older adults and 1021 younger adults were included in the analysis excluding missing values., Conclusions: Older adults with bipolar disorder use the Internet much less frequently than younger adults. Many older adults do not use the Internet, and technology tools are suitable for some but not all older adults. As more health services are only available online, and more digital tools are developed, there is concern about growing health disparities based on age. Mental health experts should participate in determining the appropriate role for digital tools for older adults with bipolar disorder.

This debate article aims to evaluate whether current diagnostic and therapeutic options for suicidal geriatric patients with depression suffice, and which adapted strategies might be helpful. We hope to encourage clinicians to consider special approaches when treating the elderly., Background: Suicide in old age is a major public health problem, as the suicide rates are highest among those aged 60 years and older in most European countries. Although pharmacological treatment options are relatively easy for older patients to obtain, their access to standard psychotherapy is limited. The reasons for this are i) the widely shared attitude about the effectiveness of psychotherapy for older people and ii) the limited access to standard psychotherapy due to their immobility., Conclusion: New psychotherapeutic methods need to be developed. Psychotherapy at the patient's home seems to be a new approach to accommodate that individual's personal circumstances and make effective therapy possible.

Background: Information seeking is an important coping mechanism for dealing with chronic illness. Despite a growing number of mental health websites, there is little understanding of how patients with bipolar disorder use the Internet to seek information., Methods: A 39 question, paper-based, anonymous survey, translated into 12 languages, was completed by 1222 patients in 17 countries as a convenience sample between March 2014 and January 2016. All patients had a diagnosis of bipolar disorder from a psychiatrist. Data were analyzed using descriptive statistics and generalized estimating equations to account for correlated data., Results: 976 (81 % of 1212 valid responses) of the patients used the Internet, and of these 750 (77 %) looked for information on bipolar disorder. When looking online for information, 89 % used a computer rather than a smartphone, and 79 % started with a general search engine. The primary reasons for searching were drug side effects (51 %), to learn anonymously (43 %), and for help coping (39 %). About 1/3 rated their search skills as expert, and 2/3 as basic or intermediate. 59 % preferred a website on mental illness and 33 % preferred Wikipedia. Only 20 % read or participated in online support groups. Most patients (62 %) searched a couple times a year. Online information seeking helped about 2/3 to cope (41 % of the entire sample). About 2/3 did not discuss Internet findings with their doctor., Conclusion: Online information seeking helps many patients to cope although alternative information sources remain important. Most patients do not discuss Internet findings with their doctor, and concern remains about the quality of online information especially related to prescription drugs. Patients may not rate search skills accurately, and may not understand limitations of online privacy. More patient education about online information searching is needed and physicians should recommend a few high quality websites.

Background: Suicidality is an individual behaviour caused by a complex framework of internal and external factors. The predictive values of personality traits for a suicide attempt have been demonstrated, especially in conjunction with Cloninger's TCI and impulsivity. Two issues remain unsolved, namely whether these traits alter over time after a suicide attempt, and how they may be influenced by depressive symptoms., Methods: We studied two patient cohorts: one sample of 81 patients after a suicide attempt no longer than 3 months previously (SA early) and another sample of 32 patients whose attempt had taken place more than 6 months previously (SA late). We carried out structured interviews with these subjects addressing diagnosis (MINI), suicidality (Scale for suicide ideation), depression (HAMD-17), temperament and character inventory (TCI), and impulsivity (BIS-10). Data analysis was done using SPSS 16.0., Results: Our two groups did not differ significantly in sociodemographics or suicidality. However, patients in the SA early group were significantly more depressed (p < 0.001), and scored lower in reward dependence (p < 0.001) and persistence (p = 0.005) but higher in harm avoidance (p < 0.001); they did not differ significantly in impulsivity (p < 0.01). Reward dependence, persistence, and harm avoidance remained significantly different between the two groups after controlling for depressive symptoms., Conclusions: Our findings suggest that some personality traits vary after a suicide attempt. Further investigations are necessary to verify our results, ideally in longitudinal studies with larger, carefully-described cohorts. It would be also clinically important to investigate the influence of therapeutic strategies on the variability of personality traits and their impact on suicidal behavior.

Background: Dietary supplements are taken by about half of Americans. Knowledge of dietary supplement use is important because they may interact with prescription drugs or other supplements, cause adverse reactions including psychiatric symptoms, or contain inherently toxic ingredients or contaminants. This study explores the use of dietary supplements by patients with bipolar disorder in the US., Methods: Data were obtained from an ongoing, naturalistic study of patients with bipolar disorder who received pharmacological treatment as usual. The patients self-reported their daily mood, sleep, and medications taken, including all drugs prescribed for bipolar disorder or that the patient felt impacted their mood. These included other prescribed drugs, over-the-counter drugs and dietary supplements. Drugs that received premarketing approval from the FDA were not included as dietary supplements. Patient demographics and daily medication use were characterized., Results: Data were available from 348 patients in the US who returned a mean 249.5 days of data. In addition to prescribed psychiatric drugs, 101 of the 348 patients (29 %) used a dietary supplement for at least 7 days and 69 (20 %) used a supplement long term (for at least 50 % of days). Of the 101 supplement users, 72 (71.3 %) took one supplement daily. The 101 patients tried over 40 different supplements, and the long-term users took 19 different supplements. The most commonly taken supplements for both groups were fish oil, B vitamins, melatonin, and multivitamins. Patients using supplements were more likely to be white (p < 0.001), older (p = 0.009), and ill for more years (p = 0.025)., Conclusions: Many patients with bipolar disorder use dietary supplements in addition to prescribed drugs. Physicians should obtain detailed information about all dietary supplements taken by patients with bipolar disorder.

Background: This study analyzed regularity in the daily dosage of antidepressants taken by patients with bipolar disorder and identified the factors associated with irregularity., Methods: Daily self-reported medication dosage taken and mood ratings were available from 144 patients who received treatment as usual. All 144 patients took the same antidepressant for at least 100 days. One hundred eleven of these patients were also taking a mood stabilizer. Approximate entropy (ApEn) was used to measure serial regularity in daily dosage. Regularity is the tendency that values within a time series remain the same on incremental comparisons. Drug holidays (missing three or more consecutive days) were also determined. Generalized estimating equations (GEE) were used to estimate if any demographic or clinical variables were associated with regularity., Results: Although the mean percent of days missing doses was only 18.6%, there was a wide range of regularity in the daily antidepressant dosage. Drug holidays were common, occurring in 41% of the analyses. Factors significantly associated with irregularity were as follows: total number of psychotropic medications (p = 0.005), pill burden (p = 0.005), and depression (p = 0.015). Neither the percent of days missing doses nor the drug holidays were associated with any demographic or clinical factors. For patients taking both antidepressants and mood stabilizers, there was no significant difference in regularity in daily dosage between these drugs., Discussion: There can be considerable irregularity in daily dosage despite a low percent of days missing doses. Medication regimen complexity and depressed mood are associated with increased irregularity. Daily regularity in drug dosage may be more dependent on the individual than on the specific drug. Research on the clinical impact of irregularity in daily dosage of antidepressants is needed.

Background: Distorted activity of the hypothalamic-pituitary-adrenocortical (HPA) system is one of the most robustly documented biological abnormalities in major depression. Lithium is central to the treatment of affective disorders, but little is known about its effects on the HPA system of depressed subjects., Objective: To assess the effects of lithium monotherapy on the HPA system of patients with major depression by means of the combined DEX/CRH test., Method: Thirty drug-naive outpatients with major depression (single episode or unipolar recurrent; SCID I- and II-confirmed) were treated with lithium monotherapy for four weeks. The DEX/CRH test was conducted directly before intake of the first lithium tablet and four weeks thereafter. Weekly ratings with the HDRS(21) were used to determine response (≥50% symptom reduction) and remission (HDRS ≤7)., Results: Lithium levels within the therapeutic range were achieved rapidly. Tolerability was good; no patient terminated the treatment prematurely. Response and remission rates were 50% and 33% respectively. Compared to the DEX/CRH test before the start of the treatment, a considerable and significant increase in all CRH-stimulated ACTH and cortisol parameters could be detected in the second DEX/CRH test. When analysed with particular regard to responders and non-responders, that significant increase was only present in the responders., Conclusions: We were able to demonstrate that lithium leads to a significant activation of the HPA system. This is possibly connected to stimulation of hypothalamic arginine vasoporessin (AVP), to direct intracellular effects of lithium on pituitary cells and to an induction of gene expression., Trial Registration: drks-nue.uniklinik-freiburg.de DRKS00003185.